Stroke is the leading cause of adult disability in America, and one of the leading causes of death in the world. If patients arrive at a hospital within 3 hours of their stroke beginning, thrombolytic therapy can be very effective. Only 40 to 50% of patients respond to lytic treatment, however, creating a priority to develop new, effective treatments for stroke. The brain consists of multiple cell types: neurons, glia, and endothelial cells, among others; during stroke, the brain loses 1.2 million neurons per minute. In the past, candidate stroke treatments that failed to benefit patients were targeted only at neurons. We now propose to test a new drug that powerfully protects neurons, glia, and endothelial cells, together known as the neurovascular unit. This drug, 3K3A-APC, acts on cells partly via the PAR-1 receptor to induce protection by several mechanisms. Multiple laboratories- using neurobehavioral and histomorphometric endpoints in several animal models-have shown the drug powerfully reduces the effects of experimental stroke, even when administered up to 4 hours after the stroke begins. In human volunteers, only mild and moderate side effects were detected at clinically relevant doses. We now propose to test 3K3A-APC-for the first time-in stroke patients who arrive at the hospital very early and receive thrombolytic treatment. Very low doses will be tried at first, and then progressively higher doses will be tried. Ultimately, we wil determine the maximum tolerated dose (MTD), that is, the largest drug dose that can be given without causing severe side effects. By the end of this study, we hope to determine a dose that is safe and well tolerated by patients suffering acute stroke. Should this study succeed, the next step would be a much larger study to test for possible benefit of 3K3A-APC in stroke patients.